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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2003
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Justification for type of information:
Read across, see declaration

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2003
Report date:
2003

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
(2S)-2-[(4R)-2-Oxo-4-propyl-1-pyrrolidinyl]butanamide
Cas Number:
357336-20-0
Molecular formula:
C11H20N2O2
IUPAC Name:
(2S)-2-[(4R)-2-Oxo-4-propyl-1-pyrrolidinyl]butanamide
Test material form:
solid: particulate/powder

Test animals

Species:
rat
Strain:
Wistar
Details on species / strain selection:
Crl:WI (Glx/BRL/Han) BR VAF PLUS strain
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Details on exposure:
Three groups of 25 male and 25 female Wistar derived rats of the Crl:WI (Glx/BRL/Han) BR VAF PLUS strain were dosed twice daily, by oral gavage, with the test article, ucb 34714. Males and females were dosed during the pre-pairing period (at least 28 days in males, 14 days in females) and the pairing period (maximum of 20 days). In addition, males were dosed post-pairing (at least 2 weeks) and females until Day 6 of gestation. The dose levels used were 100, 200 or 400 mg/kg/day, split into two equal daily subdoses given 6 hours apart. A similar group of 25 males and 25 females were dosed with the vehicle alone, 1% (w/v) methylcellulose 400 cps in sterile pyrogen-free water, following the same dosing regimen and served as Controls.
Duration of treatment / exposure:
Males and females were dosed during the pre-pairing period (at least 28 days in males, 14 days in females) and the pairing period (maximum of 20 days). In addition, males were dosed post-pairing (at least 2 weeks) and females until Day 6 of gestation.
Frequency of treatment:
The test article was administered twice daily by the oral (gavage) route as this corresponded to a proposed human therapeutic route and dose regime.
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
200 mg/kg bw/day (nominal)
Dose / conc.:
400 mg/kg bw/day (nominal)
No. of animals per sex per dose:
Three groups of 25 male and 25 female Wistar derived rats
Control animals:
yes, concurrent vehicle

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Immunological findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
The group mean number of completed oestrous cycles during the pre-pairing period was comparable with the Controls for all groups receiving ucb 34714.
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
There was no effect of treatment with ucb 34714 on sperm morphology at any of the dose levels used on this study, when compared with the Controls.
The group mean values for sperm motility, concentration, actual path velocity (VAP) and straight line velocity (VSL) were comparable with the Controls for all groups receiving ucb 34714.
Reproductive performance:
no effects observed

Details on results (P0)

There were 25, 23, 23 and 23 females (receiving vehicle Control, 100, 200 or 400 mg/kg/day respectively) that were pregnant at scheduled necrospy.
There was no effect of treatment with ucb 34714 on the group mean numbers of implantations and live embryos or on the extent of pre- and post-implantation losses. There was a statistically significant (p<0.05) increase in the mean number of corpora lutea in the group receiving 400 mg/kg/day when compared with the Controls. This was slightly above the background range of a published historical control database (MARTA / MTA = 12.1 - 13.7), but was considered to be coincidental and not of toxciological significance.

Effect levels (P0)

Key result
Dose descriptor:
NOAEL
Effect level:
ca. 400 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive function (oestrous cycle)
reproductive function (sperm measures)
reproductive performance

Target system / organ toxicity (P0)

Key result
Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
Other effects:
no effects observed

Developmental neurotoxicity (F1)

Behaviour (functional findings):
no effects observed

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
no effects observed

Details on results (F1)

The pregnancy data and early embryonic development were unaffected by the administration of ucb 34714. It is therefore concluded that the No Observed Adverse Effect Level (NOAEL) is 400 mg/kg/day for fertility and mating (both sexes) as well as for early embryonic development.

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
ca. 400 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: whole obervation

Target system / organ toxicity (F1)

Key result
Critical effects observed:
no

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
ucb 34714 was administered orally at doses of 100, 200 and 400 mg/kg/day to male and female rats during the pre-pairing period (at least 4 weeks for males and 2 weeks for females), the pairing period (maximum of 20 days) as well as post-pairing (at least 2 weeks for males and until Day 6 of gestation for females). The plasma concentrations of parent compound following repeat administrations (end of pre-pairing period) were higher in females than in males and increased less than proportionally to the dose. The only noteworthy effects consisted of a transient salivation after dosing at all dose levels in both sexes and, in males only, an increased liver weight at 200 and 400 mg/kg/day. The treatment did not induce any effects on histopathology of the testes, the stages of spermatogenesis or on sperm morphology, motility and concentration. The pregnancy data and early embryonic development were unaffected by the administration of ucb 34714. It is therefore, concluded that the No Observed Adverse Effect Level (NOAEL) is 400 mg/kg/day for fertility and mating (both sexes) as well as for early embryonic development.
Executive summary:

The study was designed to investigate the effects of the test article, ucb 34714, on fertility and early embryonic development of the rat following oral administration to males for at least 28 days prior to pairing for mating, during pairing (maximum of 20 days) and until necropsy (at least two weeks after the end of the pairing period), and to females for 14 days prior to pairing for mating, during pairing (maximum of 20 days) and to Day 6 of gestation. The total duration of treatment was at least 9 weeks for males and 4 weeks for females. Females were killed on Day 13 of gestation.

The study was conducted and the final report formatted in accordance with the known requirements of the following guideline:

Guideline on Detection of Toxicity to Reproduction for Medicinal Products. ICH Harmonised Tripartite Guideline.  Endorsed by ICH Steering Committee. Washington D.C. June 1993.

The test article, ucb 34714, is a CNS-active compound intended for the treatment of epilepsy. The test article was administered twice daily by the oral (gavage) route as this corresponded to a proposed human therapeutic route and dose regime. The rat is a suitable rodent species, acceptable to regulatory authorities as an indicator of potential hazards and for which extensive background data are available. The Crl:WI (Glx/BRL/Han) BR VAF PLUS rat is commonly used in reproduction studies because of the good fertility and fecundity of the strain.

The dose levels of 100, 200 and 400 mg/kg/day, administered as two equal subdoses given 6 hours apart were selected by the Sponsor after examining existing toxicity data and especially on the basis of results from a  13-week Oral Gavage Toxicity Study in the Wistar Rat with a 4-week recovery period (Sequani Study Number UTS0021, UCB Study Reference Number PSM0813). In that study, dose levels of 50, 100, 200 and 400 mg/kg/day were administered as two equal daily aliquots given six hours apart. The dose of 400 mg/kg/day induced liver effects, in both sexes, including increased liver weight, centrilobular hypertrophy and the presence of brown pigment identified as lipofuscin, in centrilobular hepatocytes. At this dose level there were also clinical pathology changes including increased triglycerides in both sexes and, in females, increased cholesterol and alanine aminotransferase.